Famous buildings across the world, including the Empire State Building, “Lit It Up Blue” last week for Autism Awareness Day (April 2nd).

It’s hard to imagine that only 70 years ago, autism was a brand new child psychiatric diagnosis and was considered both rare and homogenous: two adjectives that stand in stark opposition to our modern understanding of the disorder. Thus, in the midst of Autism Awareness month, I am cognizant of how much our awareness has changed and continues to change with every passing day. Although autism remains mysterious and elusive in many respects, scientists’ understanding of its root causes has evolved beyond recognition, transforming how we as a society view the autism spectrum.

Leave the past in the past (Autism research gone wrong)

Whereas most people today have a basic familiarity with autism, two-thirds of a century ago, this was not at all the case. In fact, it wasn’t even recognized as a disorder until America’s’ first child psychiatrist Leo Kanner published a seminal paper in 1943 [2]. On one hand, Kanner’s identification of the disorder gave families an explanation for their children’s abnormal development and severe language delays and led them to seek help from psychiatrists. However, Kanner also unfortunately did a lot of harm for the autism community, particularly by putting forth the idea that the disorder could be a result of “toxic parenting”. Given the psychoanalytic leanings of the day, this idea gained a regrettable amount of traction. Combined with the historical context of gender inequality (a 1948 Time article titled “Frosted Children” reported that all but five mothers of Kanner’s patients had a college degree, the horror! [2]), mothers unfortunately came to bear most of this burden under the label of “refrigerator mothers” for their supposed coldness towards their children.

This theory that autism was caused by unloving parents and mothers in particular was championed by Bruno Bettelheim (imagine the Dr. Oz of the 50’s). Through extensive forays into popular culture and his bestselling book “The Empty Fortress: Infantile Autism and the Birth of the Self”, he took control of the rover that Kanner had led off course with his initial theory of toxic parenting and tossed it out into open space. For years, individuals with autism and childhood schizophrenia1 were treated as forms of psychosis in state hospitals, and research into the neurological underpinnings of the disorder was virtually nonexistent. Thankfully, things started looking up by the mid-60’s when Bernard Rimland, a San Diego psychologist and father of a boy with autism, published a paper arguing for the first time that autism was not a form of psychosis but instead an innate “perceptual disability” [2].

Unfortunately, the theory of “toxic parenting” has not been the only one to plague the field of autism research. Most of us are all too familiar with the long-ago discredited but somehow still pervasive theory that vaccines are to blame. This was instigated by a fraudulent 1998 research paper identifying a link between the measles, mumps, and rubella (MMR) vaccine and autism. Since then, countless research has gone into debunking this myth, most recently an analysis of almost 100,000 children’s health records finding no association between MMR vaccination and autism [3]. Nevertheless, this myth somehow still persists and even reared its ugly head as recently and publicly as in the 2015 Republican presidential debates.

Despite these roadblocks, significant progress has been made in understanding the biological underpinnings of autism spectrum disorder. In the last few years in particular, new research findings have firmly established it as a biological disorder that begins before birth.

Brain, genes, and the biological causes of Autism

Research is making it increasingly clear that there is not a single cause of autism. Instead, it seems to be caused by a mix of genetic and environmental factors. For instance, a small mutation in a gene (or more likely many genes) may confer risk for autism rather than directly causing it. A recent study suggests that genetic factors account for a little over half (59%) of the risk for autism, and most of this risk comes from common mutations that are inherited (Fig 1) [4]. To make things even more complicated, whole genome sequencing of 170 families containing autistic siblings revealed that more often than not, siblings who both had autism actually had mutations in different autism-related genes [5]. This suggests not only that autism is at least as heterogeneous genetically as it is clinically, but also that genes aren’t the whole story.

Fig 1. 59% of the risk for developing autism is attributed to genetic factors, most of which are inherited genetic mutations [4].

As previously mentioned, environmental factors may sometimes make the difference between innocuous genetic mutations and full-fledged autism. By “environmental factors” I don’t mean climate change or even the social environment in which a child grows up. Instead, “environmental factors” here primarily refers to the environment in which the brain first begins to develop (after all, autism is considered a neuro-developmental disorder). For instance, many suspected environmental contributors are related to abnormal immune responses during prenatal development (and thus should not be confused with immune responses to, say, vaccines). Many genes that are altered in autism are involved in important immune signaling pathways [6]. Moreover, it has been shown that maternal infection or inflammation during early phases of prenatal development is correlated with increased autism risk [6]. However, autism is primarily a neurodevelopmental disorder, not an immune disorder, so how would abnormal immune responses lead to the alterations in the brain that underlie autism? Remarkably, just this past year, a previously unknown system of lymphatic vessels (which carry immune cells) that coat the brain were identified [7]. This astonishing discovery establishes a greater amount of direct back-and-forth between the immune system and the brain than was once believed [7]. In the coming years, more research will focus on how these brain-immune interactions may be implicated in autism.

The immune system has much closer interaction with the nervous system than was previously thought (right).

While the list of environmental risk factors is probably a long and complicated one, recent research strongly suggests that these environmental contributors must be prenatal (and hence “refrigerator parents” do not fall on this list). In brains from children with autism but not from typically-developing individuals, researchers at the Autism Center of Excellence in San Diego found abnormal “patches” of development in the prefrontal cortex – the part of the brain that is important for language, decision-making, and many important cognitive functions that have been implicated in autism (Fig 2) [8]. During the second trimester, the brain of a developing fetus undergoes an increase in the number of neurons in the cortex (the brain’s outer sheath), and these cortical neurons self-organize into distinct layers before birth. Since abnormal patches were found in these cortical layers that form during prenatal development, this provides strong evidence that people with autism are born that way.

Fig 2. Abnormal “patches” of development in the layers of the prefrontal cortex (circled) were identified in brains from children with autism [8].

Where are we now?

On one hand, we are still a long way from a full grasp of autism’s underlying causes. Although the astonishing rise of autism – from Kanner’s rare disorder to affecting more than 1% of American children today [1] – is due in large part to increasing awareness and diagnoses [9], these factors do not fully account for its dramatic increase in prevalence. Thus, much more research is still needed in order to unravel the complex genetic and environmental factors that could be contributing to this rise.

Nevertheless, let’s take a moment to appreciate how drastically our understanding of autism has changed since the days of Kanner and Bettelheim. Whereas autism was once believed to be a narrow and rare form of psychosis rooted in parental shortcomings, we now recognize it as an immensely rich and diverse spectrum disorder that results from a complex interplay between genes and prenatal environment. Strikingly, our nuanced scientific understanding has evolved and continues to evolve our societal outlook on autism as a whole. With greater appreciation for its genetic and neurological roots, we may be increasingly challenged to think of autism not as a disorder, but as a difference.

For more on Neurodiversity and the history of autism, check out Steve Silberman’s NeuroTribes: The Legacy of Autism and the Future of Neurodiversity

Footnotes:

1. As previously mentioned, the diagnosis of “autism” was initially very narrow and excluded higher-functioning individuals who might be classified as having Asperger’s today. Although Austrian pediatrician Hans Asperger, as his surname would suggest, recognized early on that there were many individuals displaying repetitive behaviors and social peculiarities who lacked the severe language impairments that Kanner reported in his patients, in the US, most individuals with Asperger’s and high-functioning autism likely fell under the diagnosis of childhood schizophrenia [2].

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For those interested: The Reuben H Fleet Science Museum in San Diego has an ongoing program called “Autism Accessibility Mornings at the Fleet” that invites the Autism Spectrum community to enjoy the museum in a quieter setting. To learn more: